Anabolic Overview 2 – Direct and Indirect Anabolic Effects

Although testosterone has been isolated, synthesized, and actively experimented with for many decades now, there is still some debate today as to exactly how steroids affect muscle mass. At this point in time, the primary mode of anabolic action with all anabolic/androgenic steroids is understood to be direct activation of the cellular androgen receptor and increases in protein synthesis. As follows, if we are able to increase our androgen level from an external source by supplementing testosterone or a similar anabolic steroid, we can greatly enhance the rate in which protein is retained by the muscles. This is clearly the primary cause for muscle growth with all anabolic/androgenic steroids. As our hormone levels increase, so does androgen receptor activation, and ultimately the rate of protein synthesis. But other indirect mechanisms could possibly affect muscle growth outside of the normally understood androgen action on protein synthesis. An indirect mechanism is one that is not brought about by activation of the androgen receptor, but the affect androgens might have on other hormones, or even the release of locally acting hormones or growth promoters inside cells (perhaps mediated by other membrane bound receptors). We must remember also that muscle mass disposition involves not only protein synthesis, but also other factors such as tissue nutrient transport and protein breakdown. We need to look at androgenic interaction with these factors as well to get a complete picture. Concerning the first possibility, we note that studies with testosterone suggest that this hormone does not increase tissue amino acid transport.9 This fact probably explains the profound synergy bodybuilders have noted in recent years with insulin, a hormone that strongly increases transport of nutrients into muscle cells. But regarding protein breakdown, we do see a second important pathway in which androgens might affect muscle growth.

Anti-Glucocorticoid Effect of Testosterone

Testosterone (and synthetic anabolic/androgenic steroids) may help to increase mass and strength by having an anti-catabolic effect on muscle cells. Considered one of the most important indirect mechanisms of androgen action, these hormones are shown to affect the actions of another type of steroid hormone in the body, glucocorticoids (cortisol is the primary representative of this group).10 Glucocorticoid hormones actually have the exact opposite effect on the muscle cell than androgens, namely sending an order to release stored protein. This process is referred to as catabolism, and represents a breaking down of muscle tissue. Muscle growth is achieved when the anabolic effects of testosterone are more pronounced overall than the degenerative effects of cortisol. With intense training and a proper diet, the body will typically store more protein than it removes, but this underlying battle is always constant. When administering anabolic steroids, however, a much higher androgen level can place glucocorticoids at a notable disadvantage. With their effect reduced, fewer cells will be given a message to release protein, and more will be accumulated in the long run. The primarily mechanism believed to bring this effect out is androgen displacement of glucocorticoids bound to the glucocorticoid receptor. In fact, in-vitro studies have supported this notion by demonstrating that testosterone has a very high affinity for this receptor,11 and further suggesting that some of its anabolic activity is directly mediated through this action.12 It is also suggested that androgens may indirectly interfere with DNA binding to the glucocorticoid response element.13 Although the exact underlying mechanism is still in debate, what is clear is that steroid administration inhibits protein breakdown, even in the fasted state, which seems clearly indicative of an anti-catabolic effect.

Testosterone and Creatine

In addition to protein synthesis, a rise in androgen levels should also enhance the synthesis of creatine in skeletal muscle tissues.14 Creatine, as creatine phosphate (CP), plays a crucial role in the manufacture of ATP (adenosine triphosphate), which is a main store of energy for the muscles. As the muscle cells are stimulated to contract, ATP molecules are broken down into ADP (adenosine diphosphate), which releases energy. The cells will then undergo a process using creatine phosphate to rapidly restore ADP to its original structure, in order to replenish ATP concentrations. During periods of intense activity, however, this process will not be fast enough to compensate and ATP levels will become lowered. This will cause the muscles to become fatigued and less able to effort a strenuous contraction. With increased levels of CP available to the cells, ATP is replenished at an enhanced rate and the muscle is both stronger and more enduring. This effect will account for some portion of the early strength increases seen during steroid therapy. Although perhaps not technically considered an anabolic effect as tissue hypertrophy is not a direct result, androgen support of creatine synthesis is certainly still looked at as a positive and growth-supporting result in the mind of the bodybuilder.

Testosterone and IGF-1

It has also been suggested that there is an indirect mechanism of testosterone action on muscle mass mediated by Insulin-Like Growth Factor. To be more specific, studies note a clear link between androgens and tissue release of,15 and responsiveness to, this anabolic hormone. For example, it has been demonstrated that increases in IGF-1 receptor concentrations in skeletal muscle are noted when elderly men are given replacement doses of testosterone.16 In essence, the cells are becoming primed for the actions of IGF-1, by testosterone. Alternately we see marked decreases in IGF-1 receptor protein levels with androgen deficiency in young men. It also appears that androgens are necessary for the local production and function of IGF-1 in skeletal muscle cells, independent of circulating growth hormone, and IGF-1 levels.17 Since we do know for certain that IGF-1 is at least a minor anabolic hormone in muscle tissue, it seems reasonable to conclude that this factor, at least at some level, is involved in the muscle growth noted with steroid therapy.

Direct and Indirect Steroids?

In looking over the proposed indirect effects of testosterone, and pondering the effectiveness of the synthetic anabolic/androgenic steroids, we must resist the temptation to believe we can categorize steroids as those which directly, and those which indirectly, promote muscle growth. The belief that there are two dichotomous groups or classes of steroids ignores the fact that all commercial steroids promote not only muscle growth but also androgenic effects. There is no complete separation of these traits at this time, making clear that all activate the cellular androgen receptor. I believe the theory behind direct and indirect steroid classifications originated when some noted the low receptor binding affinity of seemingly strong anabolic steroids like oxymetholone and methandrostenolone.18 If they bind poorly, yet work well, something else must be at work. This type of thinking fails to recognize other factors in the potency of these compounds, such as their long half-lives, estrogenic activity, and weak interaction with restrictive binding proteins (see: Free vs. Bound Testosterone). While there may possibly be differences in the way various compounds could foster growth indirectly, such that advantages way various compounds could foster growth indirectly, such that advantages might even be found with certain synergistic drug combinations, the primary mode of action with all of these compounds is the androgen receptor. The notion that steroid X and Y must never be stacked together because they both compete for the same receptor when stimulating growth, while X and Z should be combined because they work via different mechanisms, should likewise not be taken too seriously. Such classifications are based on speculation only, and upon reasonable investigation are clearly invalid.

MECHANISM OF ACTION DIAGRAM: The mechanism of anabolic
action due to the administration of anabolic/androgenic steroids. AAS
causes not only direct stimulation of the androgen receptor, but also
supports muscle growth by increasing the levels of free androgens,
increasing androgen receptor density, inhibiting corticosteroid action,
increasing GH/IGF-1, and suppressing IGF-1 binding proteins.